Getting through the matrix

The best cancer drugs in the world are not much good if they cannot get to tumor cells. That problem has been challenging cancer physicians and researchers for years because the physical structure of many tumors can prevent anticancer agents from reaching their targets. In a study appearing in the June issue of Nature Medicine, researchers from Massachusetts General Hospital (MGH) describe a new technique for assessing the permeability of tumors and a promising new way of improving tumors accessibility to drugs. The report is receiving advance online publication on the journals website at http://www.nature.com/nm/.

"Weve known for a long time that many cancer drugs work very well on cells, but not so well in patients," says Rakesh Jain, PhD, director of the Steele Laboratory for Tumor Biology at MGH, senior author of the study. "As we have improved the understanding of tumor physiology, we have found that a significant portion of a tumor is made up of an extracellular matrix that acts as a barrier, keeping drugs away from tumor cells."

This matrix is largely made up of the connective tissue collagen. To determine the structure and content of collagen in different tumor types and to assess its effect on a tumors permeability, Jains team used a new imaging technique called second-harmonic generation (SHG), a non-invasive way of measuring an optical signal released by certain molecular structures. The researchers first showed that SHG can distinguish among types of connective tissue molecules and can specifically image the structure and density of collagen fibers.

By imaging tumors that had been implanted in mice, Jains team was able to produce high-definition 3-D images that revealed the amount and form of collagen. Studying three types of tumors known to have different relative collagen contents, they showed that SHG could accurately measure collagen levels that correlated with measurements of tumor permeability. This result suggests that SHG could allow analysis of the structure and content of a tumors collagen to help with treatment planning.

To test whether SHG could measure collagen modification, the researchers first applied the enzyme collagenase, which breaks down collagen, directly to mouse tumors. Images taken after collagenase application showed significant changes in the SHG images. However, because collagen is an important part of the bodys overall structure, collagenase would not be a useful treatment adjunct since its effect could spread far beyond the tumor itself.

In their search for an agent to selectively break down tumor-matrix collagen, the research team turned to a hormone called relaxin. Naturally produced in pregnant females, relaxin increases production of enzymes associated with dilation of the cervix and other processes needed for birth preparation. Clinical trials for other potential uses of relaxin have found only minor side effects in humans.

The researchers used intravenous pumps to deliver relaxin into the bloodstream of mice with implanted human tumors and then used SHG to image the tumors over a 12-day period. They also imaged the tumors of a control group that did not receive relaxin. While the amount of collagen in the relaxin-treated tumors was similar to that seen in the control group at the end of the study period, in the relaxin-treated mice the collagen fibers had broken down and were measurably shorter. When the researchers used probe molecules to measure the tumors permeability, the results indicated that the relaxin-treated matrix tissue was looser and less of an obstacle to penetration.

"We have already started animal studies to measure whether relaxin can improve actual response to chemotherapy drugs," says Jain, who is A.W. Cook Professor of Tumor Biology at Harvard Medical School. "If those results are positive, the fact that relaxin is so safe means we could move relatively quickly into human clinical trials."

A key collaborator in this research is Brian Seed, PhD, of the MGH Department of Molecular Biology. Other authors of the report are Edward Brown, PhD, of MGH and Trevor McKee, BSc, of Massachusetts Institute of Technology, co-first authors; Emmanuelle diTomaso, PhD, and Yves Boucher, PhD, also of MGH; and Alain Pluen, PhD, of the University of Manchester in the United Kingdom. The research was supported by grants from the National Cancer Institute.

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Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $350 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Womens Hospital formed Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.

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